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Biomedical subjects

H Chi

Publications and source records attributed to H Chi.

At least 19 recordsLinked to original sources
PubMed2001

Somatic mutation and germline variants of MINPP1, a phosphatase gene located in proximity to PTEN on 10q23.3, in follicular thyroid carcinomas.

Various genes have been identified to play a role in the pathogenesis of follicular thyroid tumors. Cowden syndrome is the only known familial syndrome with an increased risk of both follicular thyroid adenoma (FA) and carcinoma (FTC). Germline mutations in the tumor suppressor gene PTEN, which encodes a dual-specificity phosphatase, have been found in up to 80% of patients with Cowden syndrome suggesting a role of PTEN in the pathogenesis of follicular thyroid tumors. Although somatic intragenic mutations in PTEN, which maps to 10q23.3, are rarely found in follicular tumors, loss of heterozygosity (LOH) of markers within 10q22-24 occurs in about 25%. Recently, another phosphatase gene, MINPP1, has been localized to 10q23.3. MINPP1 has the ability to remove 3-phosphate from inositol phosphate substrates, a function that overlaps that of PTEN. Because of this overlapping function with PTEN and the physical location of MINPP1 to a region with frequent LOH in follicular thyroid tumors, we considered it to be an excellent candidate gene that could contribute to the pathogenesis of follicular thyroid tumors. We analyzed DNA from tumor and corresponding normal tissue from 23 patients with FA and 15 patients with FTC for LOH and mutations at the MINPP1 locus. LOH was identified in four malignant and three benign tumors. One of these FTCs with LOH was found to harbor a somatic c.122C > T or S41L mutation. We also found two germline sequence variants, c.809A > G (Q270R) and IVS3 + 34T > A. The c.809A > G variant was found in only one patient with FA but not in patients with FTC or normal controls. More interestingly, IVS3 + 34T > A was found in about 15% of FA cases and normal controls but not in patients with FTC. These results suggest a role for MINPP1 in the pathogenesis of at least a subset of malignant follicular thyroid tumors, and MINPP1 might act as a low penetrance predisposition allele for FTC.

Adenoma↗
PubMed2000

Targeted deletion of Minpp1 provides new insight into the activity of multiple inositol polyphosphate phosphatase in vivo.

Multiple inositol polyphosphate phosphatase (Minpp1) metabolizes inositol 1,3,4,5,6-pentakisphosphate (InsP(5)) and inositol hexakisphosphate (InsP(6)) with high affinity in vitro. However, Minpp1 is compartmentalized in the endoplasmic reticulum (ER) lumen, where access of enzyme to these predominantly cytosolic substrates in vivo has not previously been demonstrated. To gain insight into the physiological activity of Minpp1, Minpp1-deficient mice were generated by homologous recombination. Tissue extracts from Minpp1-deficient mice lacked detectable Minpp1 mRNA expression and Minpp1 enzyme activity. Unexpectedly, Minpp1-deficient mice were viable, fertile, and without obvious defects. Although Minpp1 expression is upregulated during chondrocyte hypertrophy, normal chondrocyte differentiation and bone development were observed in Minpp1-deficient mice. Biochemical analyses demonstrate that InsP(5) and InsP(6) are in vivo substrates for ER-based Minpp1, as levels of these polyphosphates in Minpp1-deficient embryonic fibroblasts were 30 to 45% higher than in wild-type cells. This increase was reversed by reintroducing exogenous Minpp1 into the ER. Thus, ER-based Minpp1 plays a significant role in the maintenance of steady-state levels of InsP(5) and InsP(6). These polyphosphates could be reduced below their natural levels by aberrant expression in the cytosol of a truncated Minpp1 lacking its ER-targeting N terminus. This was accompanied by slowed cellular proliferation, indicating that maintenance of cellular InsP(5) and InsP(6) is essential to normal cell growth. Yet, depletion of cellular inositol polyphosphates during erythropoiesis emerges as an additional physiological activity of Minpp1; loss of this enzyme activity in erythrocytes from Minpp1-deficient mice was accompanied by upregulation of a novel, substitutive inositol polyphosphate phosphatase.

3T3 Cells↗
PubMed1999

Multiple inositol polyphosphate phosphatase: evolution as a distinct group within the histidine phosphatase family and chromosomal localization of the human and mouse genes to chromosomes 10q23 and 19.

Multiple inositol polyphosphate phosphatase is the only enzyme known to hydrolyze the abundant metabolites inositol pentakisphosphate and inositol hexakisphosphate. We have previously demonstrated that the chick homolog of multiple inositol polyphosphate phosphatase, designated HiPER1, has a role in growth plate chondrocyte differentiation. The relationship of these enzymes to intracellular signaling is obscure, and as part of our investigation we have examined the murine ((MMU)Minpp1) and human ((HSA)MINPP1) homologs. Northern blot analysis demonstrated expression of ((MMU)Minpp1 in a variety of mouse tissues, comparable to the expression of other mammalian homologs, but less restricted than the expression of HiPER1 in chick. A purified (MMU)Minpp1 fusion protein cleaved phosphate from inositol (1,3,4,5)-tetrakisphosphate and para-nitrophenyl phosphate. When the presumptive active site histidine was altered to alanine by site-directed mutagenesis, enzyme activity was abolished, confirming the classification of (MMU)Minpp1 as a histidine phosphatase. The amino acid sequences of the murine and human MINPP proteins share >80% identity with the rat enzyme and >56% identity with HiPER1, with conservation of the C-terminal consensus sequence that retains proteins in the endoplasmic reticulum. The intron/exon structure of the mammalian (MMU)Minpp1 and (HSA)MINPP1 genes is also conserved compared to the chick HiPER1 gene. Sequence analysis of plant and fruit fly MINPP homologs supports the hypothesis that the MINPP enzymes constitute a distinct evolutionary group within the histidine phosphatase family. We have mapped (HSA)MINPP1 to human chromosome 10q23 by fluorescence in situ hybridization, YAC screening, and radiation hybrid mapping. This assignment places (HSA)MINPP1 in a region of chromosome 10 that is frequently mutated in human cancers and places (HSA)MINPP1 proximal to the tumor suppressor PTEN, which maps to 10q23.3. Using a radiation hybrid panel, we localized (MMU)Minpp1 to a region of mouse chromosome 19 that includes the murine homolog of Pten. The evolutionary conservation of this novel enzyme within the inositol polyphosphate pathway suggests a significant role for multiple inositol polyphosphate phosphatase throughout higher eukaryotes.

Amino Acid Sequence↗
PubMed1999

A modular neural network architecture for pattern classification based on different feature sets.

We propose a novel connectionist method for the use of different feature sets in pattern classification. Unlike traditional methods, e.g., combination of multiple classifiers and use of a composite feature set, our method copes with the problem based on an idea of soft competition on different feature sets developed in our earlier work. An alternative modular neural network architecture is proposed to provide a more effective implementation of soft competition on different feature sets. The proposed architecture is interpreted as a generalized finite mixture model and, therefore, parameter estimation is treated as a maximum likelihood problem. An EM algorithm is derived for parameter estimation and, moreover, a model selection method is proposed to fit the proposed architecture to a specific problem. Comparative results are presented for the real world problem of speaker identification.

Humans↗
PubMed1999

[Detection of fetal DNA in maternal plasma using the nested polymerase chain reaction].

OBJECTIVE: To search for a new method of non-invasive prenatal gene diagnosis. METHODS: A single-copy human DYS14 gene of Y-chromosome of fetal DNA sequence was amplified by nested polymerase chain reaction (PCR) from twelve pregnant maternal plasma (12-40 weeks). A 239 bp and 198 bp specific fragment were obtained. The maternal plasma samples of twelve pregnant women were used directly for nested PCR. RESULTS The fragment was identified in 8 of 10 male-bearing pregnant women plasma. The diagnostic accordance rate was 80% (8/10), 6 to 8 women gave positive signals in two consecutive amplifications, 2 of 8 women gave positive signals in the second amplification. The rate of positive was increased greatly by nested PCR (from 60% to 80%). None of the other 2 female-bearing pregnant women had positive results. The final accuracy of 83.3% (10/12) was attained in all cases. CONCLUSION: The finding of circulating fetal DNA in maternal plasma may have new implications for non-invasive prenatal gene diagnosis, and the nested PCR possesses the advantages of sensitivity and specificity which improves the clinical application.

Adult↗
PubMed1996

Substance P and neurokinin A metabolism by cultured human skeletal muscle myocytes and fibroblasts.

A recent study determined that cultured human skeletal muscle adult myoblasts, myotubes, and fibroblasts degraded angiotensins and kinins via neutral endopeptidase-24.11 (NEP-24.11: EC 3.4.24.11) and aminopeptidase N (APN: EC 3.4.11.2). Due to the possible importance of other peptides to skeletal muscle blood flow and function, the present study looked specifically at the metabolism of the neurokinins substance P (SP) and neurokinin A (NKA) by skeletal muscle peptidases. The results show that SP is degraded not only by NEP-24.11, but also sequentially by dipeptidyl(amino)peptidase IV (DAP IV: EC 3.4.14.5)/APN. NKA is unaffected by DAP IV but is metabolized by NEP-24.11 and APN. NEP-24.11 was inhibited by phosphoramidon (IC50 = 80 nM), thiorphan and ZINCOV, DAP IV by diprotin A (IC50 = 8 microM), and APN by amastatin (IC50 = 50 nM) and bestatin (IC50 = 100 microM). Skeletal muscle myocyte and fibroblast metabolism of SP and NKA may regulate local skeletal muscle vascular and extravascular functions including SP- and NKA-mediated nerve-induced vasodilation. Inhibition of both NEP-24.11 and DAP IV/APN may increase skeletal muscle blood flow and decrease peripheral vascular resistance via potentiation of local neurokinin levels.

Adult↗
PubMed1996

Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant.

Missense mutations in the presenilin 2 (PS-2) gene on chromosome 1 were sought by direct nucleotide sequence analysis of the open reading frame of 60 pedigrees with familial Alzheimer's disease (FAD). In the majority of these pedigrees, PS-1 and beta-amyloid precursor protein (beta APP) gene mutations had been excluded. While no additional PS-2 pathogenic mutations were detected, four silent nucleotide substitutions and alternative splicing of nucleotides 1338-1340 (Glu325) were observed. Analysis of additional members of a pedigree known to segregate a Met239Val mutation in PS-2 revealed that the age of onset of symptoms is highly variable (range 45-88 years). This variability is not attributable to differences in ApoE genotypes. These results suggest (i) that, in contrast to mutations in PS-1, mutations in PS-2 are a relatively rare cause of FAD; (ii) that other genetic or environmental factor modify the AD phenotype associated with PS-2 mutations; and (iii) that still other FAD susceptibility genes remain to be identified.

Age of Onset↗
PubMed1996

Speaker identification using time-delay HMEs.

In this paper, we extend the Hierarchical Mixture of Experts (HME) to temporal processing and explore it for a substantial problem, that of text-dependent speaker identification. For a specific multiway classification, we propose a generalized Bernoulli density instead of the multinomial logit density to avoid the instability during training. Time-delay technique is applied for spatio-temporal processing in the HME and a combining scheme is presented for combining multiple time-delay HMEs in order to complete a multi-scale analysis for the temporal data. Using the time-delay HME along with the EM algorithm as well as the combination of multiple time-delay HMEs, the speaker identification system has a good performance and yields significantly fast training. We have also addressed some issues about the time-delay techniques in the HME.

Algorithms↗
PubMed1996

A prospective study of the clinical utility of ApoE genotype in the prediction of outcome in patients with memory impairment.

Given the relationship between the presence of ApoE epsilon 4 and Alzheimer's disease (AD), were studied whether knowledge of epsilon 4 status would predict which memory-impaired patients would develop AD over time. One hundred seven patients who presented with memory impairment but not dementia were referred to the study by their family physicians. These patients were followed prospectively over a 2-year period. Twenty-nine patients developed AD, while 78 did not develop dementia. We found that ApoE genotype was a reliable prognostic indicator of who developed AD in this group only when memory test performance was included in the predictive model. These findings indicate that limitations of ApoE genotyping in isolation as a prognostic indicator of AD. Because this study included prospectively selected patients who were followed longitudinally, our findings are likely to have more relevance in the clinical setting than those obtained from currently available retrospective studies.

Aged↗
PubMed1995

Failure to detect missense mutations in the S182 gene in a series of late-onset Alzheimer's disease cases.

The possibility of an interaction of multiple genes has been speculated in pathogenesis of Alzheimer's disease (AD). Because we have recently cloned a novel gene S182 bearing five different missense mutations which segregate with early-onset familial AD, we sought the frequency of these mutations in familial and sporadic late-onset AD to clarify the incidence of these mutations in the disease. The current study showed lack of these mutations in 118 independent subjects affected with late-onset Alzheimer's disease.

Aged↗
PubMed1995

Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene.

We report the cloning of a novel gene (E5-1) encoded on chromosome 1 which has substantial nucleotide and amino-acid sequence similarity to the S182 gene on chromosome 14q24.3. Mutations, including three new missense mutations in the S182 gene, are associated with the AD3 subtype of early-onset familial Alzheimer's disease (AD). Both the E5-1 and the S182 proteins are predicted to be integral membrane proteins with seven membrane-spanning domains, and a large exposed loop between the sixth and seventh transmembrane domains. Analysis of the nucleotide sequence of the open reading frame (ORF) of the E5-1 gene led to the discovery of two missense substitutions at conserved amino-acid residues in affected members of pedigrees with a form of familial AD that has a later age of onset than the AD3 subtype (50-70 years versus 30-60 years for AD3). These observations imply that the E5-1 gene on chromosome 1 and the S182 gene on chromosome 14q24.3 are members of a family of genes (presenilins) with related functions, and indicates that mutations in conserved residues of E5-1 could also play a role in the genesis of AD. Our results also indicate that still other AD susceptibility genes exist.

Alzheimer Disease↗
PubMed1995

Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.

Some cases of Alzheimer's disease are inherited as an autosomal dominant trait. Genetic linkage studies have mapped a locus (AD3) associated with susceptibility to a very aggressive form of Alzheimer's disease to chromosome 14q24.3. We have defined a minimal cosegregating region containing the AD3 gene, and isolated at least 19 different transcripts encoded within this region. One of these transcripts (S182) corresponds to a novel gene whose product is predicted to contain multiple transmembrane domains and resembles an integral membrane protein. Five different missense mutations have been found that cosegregate with early-onset familial Alzheimer's disease. Because these changes occurred in conserved domains of this gene, and are not present in normal controls, they are likely to be causative of AD3.

Alzheimer Disease↗
PubMed1995

Determination of serum aluminium using an ion-pair reversed-phase high-performance liquid chromatographic-fluorimetric system with lumogallion.

An ion-pair reversed-phase high-performance liquid chromatographic method with fluorimetric detection, using lumogallion [4-chloro-3-(2,4-dihydroxyphenylazo)-2-hydroxybenzene-1-sulphonic acid] as a ligand, has been successfully applied to the determination of aluminium in human serum. The highly fluorescent aluminium-lumogallion complex (lambda ex 505 nm, lambda em 574 nm) was separated on a LiChrosorb RP-18 column with an eluent consisting of 30% acetonitrile, 70% 0.02 M potassium hydrogen phthalate and 10 microM lumogallion. The proposed system offers a simple, rapid, selective and sensitive method for the determination of aluminium in serum. The detection limit for aluminium was 0.05 microgram/l in aqueous solution and the limit of determination was 2.2 micrograms/l in serum. The recovery of the method is generally over 90%.

Aluminum↗